NO178485B - Process for preparing a pharmaceutical granulate - Google Patents

Abstract

A wet granulate is provided containing a therapeutically useful substance having a water solubility 10 wt% or less and microcrystalline or microfine cellulose or a mixture of both, characterised in that substantial amounts of wet binders are avoided. Tableting mixtures with the new granulate possess a good flow pattern and may be compressed to tablets which show an excellent disintegration behaviour.

Description

The present invention relates to a method for producing a pharmaceutical preparation which can pass through flow cup openings which are not larger than 12 mm during wet granulation without interruption. The granulate has improved flow properties and the tablets that can be produced have improved dissolution.

The effect of drugs is based on the presence of an active principle, a therapeutically useful compound. As a rule, the active principle should be mixed with other compounds, which may themselves be therapeutically active, or which are necessary for excipients for the preparation of the correct dosage form. In the case of pharmaceutical operations, in which the powder is involved,

it is important that the powder has good flow properties. Many therapeutically useful compounds, on the other hand, cannot be easily processed into dosage forms, especially tablets or capsules, because they have an inherently unsatisfactory flow behavior. Therefore, those compounds are first converted into a granule with the desired flow properties according to well-established pharmaceutical practice before tableting. The present invention relates to wet granulation, in which the active principle is mixed with a granulation liquid which is often water, and to which special granulation aids can be added. According to well-known methods, a wet mass is passed through a sieve, coarsely ground, dried, ground and sieved. The granules produced in this way can, for example, be used as an ingredient in a tablet mixture, but when capsules are the chosen dosage form, the granules themselves can be used.

In order to impart a firm consistency to the granules, according to standard practice a wetting compound (wetting agent) should be added to the granulation mixture, especially when the granules should contain a relatively large amount of active principle. Further information in this field can be found, for example, in H.A. Lieberman and L. Lachman, Pharmaceutical Dosage Forms (1980), vol. I, pp. 113-116 ("Wet granulation") or in L. Lachma, H.A. Lieberman and J.L. Kanig, The Theory and Practice of Industrial Pharmacy, 3rd Ed., pp. 320-324 ("Wet Granulation"). Examples of wet binding agents are acacia gum, gelatin, polyvinylpyrrolidone, starch (paste and pre-gelatinized), sodium alginate and alginate derivatives, sorbitol, glucose and other sugars, tragacanth and soluble celluloses such as methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and hydroxypropyl cellulose. Wetting agents are usually added to a granulation mixture in amounts of 1-10 wt-# with respect to the active principle. Although the use of a spring-binding compound for granulation is considered necessary to provide a good granule, it appears that tablets prepared from such granulates exhibit poor dissolution behavior when immersed in water. This can be a disadvantage when it comes to biological absorption. The therapeutically useful compound is released from tablets that rapidly dissolve in a very short time, with the effect that absorption and therapeutic action begin earlier and higher initial drug concentrations in the body are achieved.

Chalmers and Elworthy (J. Pharm. Pharmacol. (1976) 28 p 234-238) describe properties of tablets prepared by compression of granules containing a tetracyclic antibiotic and 7.2 wt # of microcrystalline cellulose and are prepared by either: 1. a conventional wet granulation process using 30$ w/w water, without a wet granulation binder, as granulation liquid, or 2. "slugging" after dry mixing of the ingredients. The disintegration time of the tablets prepared according to the first method is 14.7 minutes and 1.9 minutes for those prepared according to the second method.

EP-A-0 255404 describes a sustained release formulation consisting of coated granules containing ibuprofen and 20% microcrystalline cellulose. The core of the granules is produced by mixing ibuprofen and microcrystalline cellulose with 6056 water, extruding the wet mass, forming spherulates and drying.

The present invention therefore relates to a method for the production of a pharmaceutical preparation which can continuously pass through flow cup openings which are not larger than 12 mm during wet granulation, characterized by the following steps: a. mixing a therapeutically useful compound, which is not a tetracycline antibiotic, which has a solubility in water of less than 10 wt-#, 20-100 wt-# of a cellulose product, which is microcrystalline cellulose or microfine cellulose or a mixture of both, and 0-0.5 wt-# of a wet granulation binding compound, with 40-135 wt-# of an aqueous granulation liquid to form a wet mass, the percentages of the excipients being based on the therapeutically useful compound; b. processing said wet pulp to form a granule; c. passage of said wet mass through a first sieve; d. drying the sieved granulate;

e. passing the dried granulate through a second

sight and

f. collection of the resulting granulate.

g. preparation of a pharmaceutical dosage form of the granulate, possibly after mixing the granulate with other excipients.

The aim of the present invention is therefore to provide by means of the method a granule of good quality, despite the fact that it contains a relatively large amount of active compound, which can further be processed into solid tablets with a satisfactory dissolution behavior.

It has surprisingly been discovered that using wet granulation, a granule of good quality can be prepared from a therapeutically useful compound, present in high concentrations, but with limiting solubility in water of less than 10 wt-56, together with a cellulosic product, which may be microcrystalline cellulose or microfine cellulose or a mixture of both, but without the addition of a significant amount of a wet-binding compound. The granules produced according to the invention pass continuously through flow cup openings no larger than 12 mm, and often even smaller.

In order to provide the granulate, a wet granulation process is used which is also known in the field. The invention can be used with many types of therapeutically useful compounds, such as beta-lactams, antibiotics, tetracyclines, steroids, etc., provided that their solubility in water is less than 10 wt-#, and preferably less than 5 wt-#. For example, the following therapeutically useful compounds can be successfully granulated according to the invention: Amiodarone, amoxicillin, cimetidine, chloramphenicol, cotrimoxazole, doxycycline monohydrate, erythromycin ethylsuccinate, flumequin, furazolidone, hydrotalcite, ibuprofen, indomethacin, L-dopa, naproxen , paracetamol, penicillin V acid, pipemidic acid, piroxicam, progesterone, proligeston, ox-cytetracycline dihydrate, sulfamethoxazole, sulindac, spironolactone, theophylline and trimethoprim.

The granulation mixture is preferably prepared by first mixing the active principle with microcrystalline cellulose or microfine cellulose or a mixture of both. Microfine cellulose is the common name for purified, partially depolymerized cellulose that occurs as a crystalline powder, including porous particles. It is a widely used excipient, known for example under the brand name "Avicel". Some Avicel grades, notably Avicel RC-581, contain the wet binder sodium carboxymethylcellulose in an amount of about 11 wt-56. But according to the present invention only microcrystalline cellulose with less than 10 wt-#, if a wet binder, (preferably of "Avicel PH-102) is used. Microfine cellulose, for example "Elcema™, also known as cellulose in powder form, is a mechanical processed alpha-cellulose derived from fibrous plant material. It is a common pharmaceutical binder and solvent. In this specification and the appended claims, "cellulose product" refers specifically to microcrystalline cellulose and microfine cellulose and to mixtures thereof. The cellulosic product may be used in amounts of 20-100 wt.-preferably 35-45 wt.-# based on the weight of the therapeutically useful compound.

Various granulating liquids are known and can also be used, for example methylene chloride and isopropyl alcohol, but water is preferably used. The amount of granulation liquid may be 40-135 wt-#, preferably 60-90 wt-#, based on the weight of the therapeutically useful compound.

Use of a wetting compound such as those described above in the granulation mixture should be avoided or limited to an amount of not more than 0.5% by weight, preferably less than 0.1% by weight based on the weight of the therapeutic active connection. If not, the dissolution behavior of the tablets prepared from the granulate is adversely affected.

While many of the above-mentioned therapeutically useful compounds have unsatisfactory flow characteristics, resulting in tablet compositions that are difficult to process, the new granulate and the compositions prepared with the new granule have a significantly improved flow pattern. According to a standard test, which has not yet been described, the smallest flow cup opening through which the powder can continuously flow is no larger than 12 mm and often even smaller.

The granules produced according to the invention disperse quickly in water. Tablets prepared from the granulate and, optionally, one or more excipients, also show a very good dissolution behavior when immersed in water at about 20°C, which normally results in a perfect suspension without large lumps within 60 seconds.

The flow behavior of the granules produced according to the invention and of the tablet mixtures containing these granules can be quantified by using as a parameter the opening diameter of the opening of a cup, referred to as a flow cup, through which the powder flows continuously. If a powder can flow uninterrupted through an opening of 2.5 mm, the flow behavior is graded "excellent".

The cylindrical glass flow cups have a length of approximately 65 mm and a diameter of approximately 39 mm. The base is conical in shape with a central round opening. Silicon-coated cups are partially (about half) filled with powder. The test procedure allows the powder movement to be initiated by tapping the flow cup, but after this the powder should flow continuously out of the cup until it is empty. The graduations used are:

The invention is further illustrated by means of the following examples.

All percentages, unless otherwise stated, are based on the weight of the therapeutically active compound.

The indicated dispersion times refer to tablets prepared with granules according to the formulation in Example 28 and using water at approximately 20°C for dissolution.

eps means centipoise.

Low-substituted hydroxypropyl cellulose is designated LH 11 or 1-HPC.

EXAMPLES 1-27

The pharmaceutical compounds according to the following tables are mixed with either 40 wt-& (table 1) or 100 wt-#

(table 2) microcrystalline cellulose (AVICEL PH-102) and the amount of water is as indicated in tables 1 and 2. The resulting wet mass is sieved through a sieve with a 2 mm mesh size and dried in a fluidized sieve dryer at approximately 60° C for about an hour. The resulting dry granulate was sieved through a sieve with a mesh size of 0.8 mm and collected.

Comparative experiments

In a comparative experiment, 300 g of microcrystalline cellulose and 300 g of a compound selected from the group consisting of minocycline hydrochloride, cimetidine and trimethoprim were mixed together and granulated with about 50% water to form a wet slurry. A portion was passed through a 2 mm mesh sieve, dried, sieved through a 0.8 mm mesh sieve (Procedure A) and compressed into tablets of approximately 1130 mg with a diameter of 15 mm and a hardness of 100-150 N after mixing the granules with other excipients. The remaining portion was extruded through a cylindrical shaped plate with 1.0 mm holes, dried, sieved through a 0.8 mm mesh sieve (Procedure B) and compressed into tablets of approximately 1130 mg with a diameter of 15 mm and a hardness of 100-150 N after mixing the granulate with other excipients.

The composition of the tablets was:

The disintegration time of the tablets in water at 20"C was:

EXAMPLE 28

The granules obtained according to the previous examples were used to press tablets in the usual way using the following mixture:

90.25 g granules

1.45 g of microcrystalline cellulose

5.34 g low-substituted hydroxypropyl cellulose 2.00 g flavourings

0.16 g colloidal silica gel

0.80 g magnesium stearate

Each tablet mixture was passed through the flow cups of the test to determine the smallest flow cup opening through which each mixture could flow continuously. The results are listed in tables 1 and 2.

The resulting 15 mm tablets had a hardness of 100-150 N and a dissolution time as shown in Tables 1 and 2 above. This time was determined using the standard USP disintegration tester (ERWEKA).

EXAMPLE 29

200 g of amoxicillin trihydrate was mixed with 80 g of microfine cellulose (ELCEMA G400) and 150 ml of water. The resulting wet mass was kneaded for 20 minutes, sieved through a 2 mm mesh screen and dried in a fluidized sieve drier at about 60°C for about 1 hour until the granules contained no more than 10.5 wt-# of water. The resulting dry granules were sieved through a 0.8 mm sieve and collected.

EXAMPLE 30

The granulate was mixed for 10 minutes with the other additives and the resulting mixture was compressed into tablets on a rotary press. The 960 mg tablets produced had a hardness of 106 N and dissolved in water at 20°C within 40 seconds.

EXAMPLE 31

100 g of amoxicillin containing granules from example 2

6.18 g microcrystalline cellulose (AVICEL PH-102) 6.18 g cross-linked polyvinylpyrrolidone

(COLLIDON CL)

0.19 g colloidal silica gel

0.93 g of magnesium stearate

According to the procedure in Example 30, 955 mg tablets were provided with a hardness of 107 N and a dissolution time of 26 seconds in water at 20°C.

EXAMPLE 32

Doxycycline monohydrate (105.8 g) and microcrystalline cellulose (AVICEL PH-102) (45 g) were mixed for 15 minutes in a powered mixer. The mixture was granulated with 60 ml of water. After 10 minutes of kneading, the resulting wet mass was passed through a 2 mm sieve and the wet granules were dried at about 40°C until the water content was below 2%. The granulation was passed through a 0.71 mm sieve and mixed for 20 minutes with 1ite-substituted hydroxypropyl cellulose LH11 (18 g), hydroxypropyl methyl cellulose 5 eps (4 g), saccharin (10 g), colloidal silica gel (0.6 g) and enough lactose to bring the total weight to 248 g. Then magnesium stearate

(2 g) was added and mixing was continued for another 2 minutes. The resulting mixture was compressed to

tablets of 250 mg, approximately 9 mm in diameter and a hardness of

68-97 N or into tablets of approximately 125 mg with a hardness 5 of 58-87 N. They were completely dissolved in water at 20°C within 30-45 seconds.

10 EXAMPLES 33-36

The pharmaceutical compounds according to Table 3 were mixed with 40 wt # of microcrystalline cellulose (AVICEL PH-102) and

0.1 wt # polyvinylpyrrolidone (PVP K30, average molecular weight 49,000). The resulting mixture was granulated by mixing with the amount of water indicated in Table 3. The resulting mass was passed through a 2 mm sieve, and then dried overnight at 60°C. The dried mass remained

passed through a 0.8 mm sieve and collected.

20

EXAMPLE 37

The granules provided according to examples 33-36 were used to press tablets using the following mixture:

The flow properties of each tablet mixture were determined with the flow cups. The smallest opening through which each mixture could flow uninterrupted is listed in Table 3. Tablets of 1130 mg were pressed with a diameter of 15 mm and a hardness of 100-150 N. The dissolution times in water at 20° C were measured using by the USP disintegration tester (ERWEKA). The results are shown in table 3.

EXAMPLE 38

7.145 g of erythromycin ethyl succinate was mixed with 0.0071 g of PVP K30 and 2.86 g of microcrystalline cellulose. The mixture was wet granulated using 5 ml of isopropyl alcohol. The resulting granulate was passed through a 2 mm sieve and then dried overnight at 60°C. The dried granulate, after passing through a 0.8 mm sieve, flowed continuously through a flow cup with an opening of 8 mm. 9 g of the granulate was mixed with:

The resulting tatlet mixture flowed continuously through a 5 mm orifice.

Tablets of 1130 mg (with a diameter of 15 mm) were pressed with a hardness of 100-150 N.

The dissolution time of the tablets in water at 20° C was 40-50 seconds.

Claims (10)

1. Process for the preparation of a pharmaceutical preparation which can continuously pass through flow cup openings no larger than 12 mm in wet granulation, characterized by the following steps: a. mixing a therapeutically useful compound, which is not a tetracycline antibiotic, which has a solubility in water of less than 10 wt-#, 20-100 wt-# of a cellulosic product, which is microcrystalline cellulose or microfine cellulose or a mixture of both, and 0-0.5 wt-# of a wet granulation binder, with 40-135 wt - # of an aqueous granulation liquid to form a wet mass, wherein the percentages of the excipients are based on the therapeutically useful compound; b. processing said wet pulp to form a granule; c. passage of said wet mass through a first sieve; d. drying the sieved granulate; e. passing the dried granulate through a second sieve and f. collecting the resulting granulate. g. preparation of a pharmaceutical dosage form of the granulate, possibly after mixing the granulate with other excipients. 2. Method according to claim 1, characterized in that the granulate comprises at least 50% by weight of the therapeutically active compound. 3. Method according to claim 1 or 2, characterized in that the granulate contains 0-0.1 wt-# of a wet granulation binding compound based on the therapeutically active compound. 4. Method according to any one of claims 1-3, characterized in that the therapeutically active compound has a solubility in water of less than 5% by weight. 5. Method according to any one of claims 1-4, characterized in that the granulate contains 35-45% by weight of the cellulose product based on the therapeutically active compound. 6. Method according to any one of claims 1-5, characterized in that 60-90% by weight of the granulation liquid is used. 7. Method according to any one of claims 1-6, characterized in that the therapeutically useful compound is an amphoteric beta-lactam antibiotic. 8. Method according to any one of claims 1-6, characterized in that the therapeutically useful compound is hydrotalcite. 9. Process according to any one of claims 1-8, characterized in that the granulate is mixed with 1.9-17.1 wt-# of the cellulose product and 7.4-17.1 wt-# of a solvent, and possibly other excipients, in that all the percentages are based on therapeutic useful compound, and that tablets are formed from the mixture. 10. Method according to claim 9, characterized in that the solvent is low-substituted hydroxypropyl cellulose or cross-linked polyvinylpyrrolidone.